Synthesis and biological activities of ftorafur metabolites. 3'- and 4'-Hydroxyftorafur

Abstract

Four isomers of ftorafur were synthesized as authentic samples of possible ftorafur [an antitumor agent] (FT) metabolites. 2,3-Dihydrofuran was treated with perbenzoic acid in MeOH to give 2-methoxy-3-hydroxytetrahydrofuran, which upon treatment with Ac2O/pyridine yielded the key intermediate 2-methoxy-3-acetoxytetrahydrofuran. The other intermediate, 2-ethoxy-4-acetoxytetrahydrofuran, was prepared by acid hydrolysis (HCl/50% EtOH) of 1,1-diethoxy-3,4-dihydroxybutane, followed by acetylation (Ac2O/pyridine). Treatment of 2,4-bis(trimethylsilyl)-5-fluorouracil with either 2-methoxy-3-acetoxytetrahydrofuran or 2-ethoxy-4-acetoxytetrahydrofuran in 1,2-dichloroethane at room temperature using SnCl4 as catalyst afforded cis- and trans-3''-OAc-FT or 4''-OAc-FT, respectively; trans-3''-OAc-FT and cis-4''-OAc-FT were the major condensation products. In each case, separation of these cis and trans isomers was achieved by silica gel column chromatography. Treatment of 3''- or 4''-OAc-FT with NH3/CH3OH at 5.degree. C overnight yielded the desired hydroxylated FT. Both trans-3''-OH-FT and cis-4''-OH-FT showed no significant activity against mouse leukemia L1210 up to 100 mg/kg. These 2 agents produced an inhibitory effect on [human cervical carcinoma] HeLa cell growth equal to that of ftorafur, with ID50 = 200 .mu.g/kg.